PROJECT SUMMARY/ABSTRACT Alzheimer's Disease (AD) is a devastating neurodegenerative disease that results in severe lifelong disability and has an enormous impact on both the public health costs and burden of care. Late-onset AD is characterized by a decade-long preclinical phase and eventually leads to mild cognitive impairment (MCI) as its first clinical manifestation. This is a critical period for early intervention that determines long-term outcome. Early quantitative biomarkers can play an important role in such efforts. Olfactory deficits are a core feature and pre-clinical sign of AD. The olfactory system provides direct access to orbitofrontal-limbic neurocircuitry implicated in AD and holds unique promise for understanding neurodegenerative process. However, comparatively little is known about this system when weighed against existing knowledge of the visual and auditory sensory modalities. Psychophysical testing remains the gold-standard method for assessment of the sense of smell in humans. The results from these tests can be subjective and uninformative regarding the underlying physiological abnormalities of the ol- factory system. Therefore, it is of great importance to improve our understanding of the underlying neurophysi- ological substrates of olfactory function in AD. To this end, we propose in this supplement to employ advanced MR imaging approaches developed in our parent R01 project to acquire pilot data on small blood and lymphatic vessel abnormalities in the olfactory system in MCI. In the brain, small arterioles with diameters up to 100-150 microns are the primary regulator of local tissue perfusion. Lymphatic vessels have also been identified in the brain, which are believed to play a crucial role in the clearance of waste products. Quantitative measurement of the small blood and lymphatic vessels in the olfactory system would provide biologically meaningful information on olfactory loss and would significantly enhance efforts for the prediction and staging of brain diseases. This pilot study will involve the acquisition of data for 20 MCI patients and 20 age-matched healthy controls. MRI images will be acquired using the same approaches developed in the parent R01 to characterize changes in small blood and lymphatic vessels in the olfactory system in MCI patients and controls. Furthermore, the rela- tionship between MRI measures and behavioral olfactory task performance and established CSF markers for AD will be assessed. This study, if successful, may facilitate the development of potential biomarkers of AD in hu- mans that are related to key preclinical symptoms and underlying pathophysiology of the disease. We believe that this represents a natural extension of the proposed work in the parent R01, and a highly effective way to utilize the resource provided by the parent R01 and to maximize the impact of the research. While this limited data set will not allow conclusive results with respect to MCI and AD, it will allow us to get a first preliminary data set to judge the feasibility of a larger study for which we would request funding through the R01 mechanism using the data.